Cocaine abuse during pregnancy has increased dramatically in association with intrauterine growth retardation, placental abruption and premature delivery. The objective of the proposed research is to investigate cellular and biochemical alterations in the placenta which are associated with exposure to cocaine during pregnancy. Our recent studies with human and rat placenta indicate that exposure to cigarette smoke, and isolated constituents of cigarette smoke, are associated with selective alterations in receptors for growth factors. The proposed research will use a related approach to investigate the effects of cocaine on placental growth. The first specific aim will investigate whether the administration of cocaine to pregnant rats has dose-dependent effects on placental weight. Isolated labyrinth, basal zone and decidua portions of the placenta will be weighed and examined histologically for evidence of hemorrhage and abruptions. Concentrations of cocaine and its major metabolites will be measured in maternal and fetal plasma. Data will be analyzed to determine if there are dose-dependent relationships between amount of cocaine administered, maternal plasma cocaine levels, and placental growth. The second specific aim will examine whether cocaine exposure alters growth factor receptors at the maternal-fetal interface. EGF and insulin receptor binding and receptor autophosphorylation will be characterized in basal zone and decidua portions of placental tissue following maternal exposure to doses of cocaine which produce placental growth retardation. Insofar as no fetal vascular elements are present in basal zone tissue, these studies should provide evidence of changes related only to maternal vascular supply. Cultured rat trophoblast cells will be used to examine whether cocaine exposure in vitro has direct effects on EGF and insulin receptors. The third specific aim of the proposed research will investigate whether cocaine exposure alters placental peptide hormone synthesis. The synthesis of rat placental lactogen II, rat prolactin-like proteins A and B, and pregnancy specific-beta1 glycoprotein will be studied in basal zone tissue from pregnant rats administered cocaine. Maternal serum levels of these placental proteins will also be measured. These experiments will provide information on whether there is a dose- related effect of cocaine on placental protein synthesis, or possibly a relationship between maternal plasma levels of cocaine and circulating placental proteins. Specific aim four wil investigate whether cocaine alters cytokine production at the maternal-fetal interface. The production of granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte colony-stimulating factor (CSF-1) and transforming growth factor beta (TGF-beta) by maternal decidua and fetal basal zone tissue wil be quantitated by bioassay and immunologic procedures. The experiments will provide important information on whether cocaine has potential immuno- suppressive effects on placental cytokine production. If cocaine does suppress decidual production of GM-CSF and/or CSF-1, the final specific aim will examine if cytokine therapy will reverse the placental and/or fetal toxicity when co-administered with cocaine to pregnant rats. In summary, the proposed research will evaluate several in vivo and in vitro models of toxicity of cocaine in the rodent placenta.